During the late 19th century, Creedmoor served as a railroad depot between the Clarksville and Oxford Railroad and the Raleigh and Gatson Railroad.

A post office was granted in 1886; John Harmon served as the first postmaster and was succeeded by his son, Thomas B. Lyon.

Creedmoor was incorporated in 1895 as Creedmoore, and was reincorporated in 1905 as Creedmoor. Joseph L. Peed was the first mayor. Dr. J. F. Sanderford, Isaac Bullock, S.C. Lyon, Claude V. Garner and L. H. Longmire were the first commissioners.

Creedmoor was, at one time, a larger tobacco market than Durham. In addition to tobacco, farmers in the area grew cotton.

At one time Creedmoor was known as "Mule Town," functioning for a time as the largest "mule trading center" in the world.